Alzheimer's disease (AD) is a dementia that affects 4 million elderly individuals in the USA and this number is projected to quadruple by 2050. This neurodegenerative disorder strikes 4% of individuals at 65 years of age and as many as 40% of those at age 85 at a cost of over $100 billion annually. There is an urgent need for effective therapeutic interventions that may prevent, delay the age of onset or relent the course of this dementia. Transgenic (Tg) mice expressing human AD genes such as amyloid- precursor protein (APP), presenilin (PS), the microtubule protein tau, -amyloid cleaving enzyme-1 (BACE-1), and a-synuclein have provided tools to investigate both the pathogenesis and the efficacy of treatments for these neuropathological disorders. Our goal, in Specific Aim 1, is to better understand the strengths and limitations of several Tg mice models by establishing the degree of biochemical similarities and differences between these paradigms and human AD subjects. In Specific Aim 2, soluble and deposited A remaining after anti- A active and passive immunizations of AD patients will be quantitatively and qualitatively assessed in gray and white matter and cerebral vasculature to evaluate the effects of immunization on A dynamics and its clinical impact on the course of AD. In Specific Aim 3, the APP and A peptides retained in the brain microsomal, mitochondrial and lipid raft brain fractions in AD and non-demented controls will be determined to better understand the role of neuronal and glial participation in the pathophysiology of AD. To achieve these three objectives physicochemical techniques involving the use of density and affinity gradients, chaotropic agents, multiple chromatographic separations, amino acid analysis, peptide sequencing, mass spectrometry, bioinformatics data bases, immunoassays and Western blotting will be implemented. The proposed studies will: 1) aid in the accurate interpretation of Tg mouse experimental responses, 2) help to elucidate at the molecular level the direct and indirect effects of anti- A immunization and 3) discover the pathological consequences, beyond soluble A and deposited amyloid, of membrane-retained APP/ A peptides. A more complete understanding of AD molecular phenotypes and their clinical responses will aid in the discovery and application of efficacious treatments that will prevent AD or enhance the quality of life of AD patients. PUBLIC HEALTH RELEVANCE: More than 5 million Americans already suffer from Alzheimer's disease and this number is expected to quadruple by the year 2050, making the development of effective remedial interventions to prevent, delay the onset or slow the progression of this devastating dementia a national imperative. We know neither the cause nor posses a means to cure AD today, but meticulous chemical studies of human brains and animal models will help to elucidate the fundamental molecular basis of Alzheimer's disease and reveal the precise pathological changes that occur in the human brain during the development of this disease. This knowledge will provide the essential bases for the development of the next generation of medicinal interventions that will prevent Alzheimer's disease or enhance the quality of life of individuals with this dementia.